DESCRIPTION: The goal of the proposed project is to establish the role of the calcium-sensing receptor (CaR) in regulating the proliferation of fibroblasts, and to define the signal transduction pathways interacting with the CaR. To accomplish this, Dr. Rodland's research plan has four specific aims: 1) To determine whether release of intracellular calcium is required for downstream signaling from the CaR (e.g. activation of c-Src and, ultimately, activation o ERK kinase); 2) To determine whether Src activation, Shc phosphorylation, and p62dok association with RasGAP are required for CaR-dependent activation of ERK1; 3) To determine whether Ras activation and stimulation of the Ras-Raf-Me cascade are required for CaR-dependent activation of ERK1; 4) To determine which responses to extracellular calcium are dependent on expression of the CaR, using CaR null fibroblasts generated from knock-out mice. These aims will be accomplished through experiments using specific inhibitors and dominant negative mutants of the key participants in the hypothesized signaling pathway